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Title The biology and total syntheses of bisbenzylisoquinoline alkaloids.

Permalink https://escholarship.org/uc/item/67s758hb

Journal Organic & biomolecular chemistry, 19(35)

ISSN 1477-0520

Authors Nguyen, Viviene K Kou, Kevin GM

Publication Date 2021-09-15

DOI 10.1039/d1ob00812a

Peer reviewed

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REVIEW

The biology and total syntheses of bisbenzylisoquinoline alkaloids

Viviene K. Nguyen, Kevin. G. M. Kou*

Received 00th January 20xx, Accepted 00th January 20xx

DOI: 10.1039/x0xx00000x This mini-review provides a concise overview of the biosynthetic pathway and pharmacology of the bisbenzylisoquinoline alkaloid (bisBIA) natural poducts. Additional emphasis is given to the methodologies in the total syntheses of both the simpler acyclic diaryl ether dimers and their macrocyclic counterparts bearing two diaryl ether linkages.

1. Introduction and classification The benzylisoquinoline alkaloids (BIAs) represent a family of over 2500 plant natural products that have been used for centuries as analgesics and wound disinfectants.1 Some of the active and biosynthetically-related members, have been exploited in modern medicine, for example, morphine for pain, 2 colchicine for gout, and noscapine for cough and cancer. In Figure 1. Coclaurine (1 and 2) and/or reticuline (3) are the recent years, the pursuit of bisbenzylisoquinoline alkaloids biosynthetic building blocks of the majority of bisBIAs. (bisBIAs), molecules comprising two BIA motifs, is gaining traction. Isolated from the Berberidaceae, Ranunculaceae, their botanical sources as well as spectral and physical data.1-8 Lauraceae and Menispermaceae plant families, these This review highlights the biosynthesis and medicinal compounds can modulate diverse biological functions.3,4 With implications of bisBIAs. Further attention is given to the varied and rich pharmacology and chemistry, the majority of prevailing synthesis strategies for preparing these alkaloids. these alkaloids arise from the condensation of two coclaurine units (1 or 2) while some can arise from the condensation of a coclaurine with reticuline (3, Figure 1).5,6 Based on these 2. Biosynthesis distinctions, bisBIAs are often divided into three major classes: BisBIAs come from a highly conserved biosynthetic 7 bisreticulines, coclaurine-reticulines, and biscoclaurines. pathway.8 Catalyzed by tyrosine decarboxylase, the In all instances, the two benzylisoquinoline moieties are biosynthesis begins with the conversion of amino acid (S)- linked via biphenyl, diphenyl ether, or benzyl phenyl ether tyrosine (4) into 4-hydroxyphenylacetaldehyde (5) and 7 bonds. Aromatic rings with hydroxy, methoxy or dopamine (6, Figure 2).8,9 A Pictet–Spengler transformation methylenedioxy substituents and two chiral centers make up facilitated by the enzyme norcoclaurine synthase combines the key features of bisBIAs. Therefore, a high degree of variation arylacetaldehyde 5 with dopamine (6) to generate (S)- is observed depending on the number of ether linkages, the norcoclaurine. After two successive enzymatic O- and N- sites on the two units at which the linkage originates, the nature methylation steps, the core intermediate N-methylcoclaurine of substitution of the nitrogen atoms, and the degree of (2) is attained that ultimately gives rise to an array of BIAs. unsaturation with regard to the heterocycles. For simple bisBIA derivatives, two N-methylcoclaurine units Currently, over five hundred bisBIAs are known and have are oxidatively dimerized via the P450 enzyme CYP80A1.8,10 since been the subject of several review articles detailing their More complex cyclic bisBIAs are produced following a series of downstream biosynthetic modifications that lead to the introduction of additional functionality. Even so, and as noted by Weber and Opatz, the observed structural diversity of bisBIAs is not entirely substantiated by our current * Department of Chemistry, University of California, Riverside, California 92521, 8 United States understanding of their biosynthesis. For example, the See DOI: 10.1039/x0xx00000x

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Figure 2. Current understanding of the bisBIA biosynthetic pathway. enzyme(s) responsible for the formation of sterically OC43) replication in MRC-5 human lung cells.22 Likewise, the encumbered, electron-rich diaryl ether bonds of cyclic bisBIAs approved bisBIA drug cepharanthine (11) was shown to inhibit such as tetrandrine (8) and berbamine (9) from berbamunine SARS-CoV-2 replication with minimal toxicity at a half maximal 11,12 (7) has not been identified. 23,24 effective concentration (EC50) of 0.35 µM (Figure 3). While the mechanism of action of cepharanthine (11) is multifaceted, 3. Biological activity the antiviral activity not only relies on suppression of nuclear factor-κB (NF-κB) signaling pathways but also induction of Bisbenzylisoquinoline alkaloids have drawn significant plasma membrane rigidity to hamper entry of the pathogen into attention due to their potent anti-inflammatory, antiviral, the cell.23 These activities highlight a new role for bisBIAs in the antitumor, analgesic and antiplasmodial properties.6 prevention and treatment of SARS-CoV-2 infection. Though Formulations containing these alkaloids have been used for many bisBIAs have yet to be biologically evaluated, some centuries as traditional medicines in India, China, sub-Saharan demonstrate potential as drug candidates and merit special Africa and Southeast Asia.13 Some active members even have emphasis: tetrandrine (8), berbamine (9), neferine (12), and the ability to immobilize skeletal muscle, hence their dauricine (13, Figure 3). pronounced use as arrow poisons in South America.14 While a detailed analysis of the pharmacology is beyond the 3.1 Tetrandrine scope of this review, the quantity of publications concerning the First isolated by Kondo and Tano in 1928, tetrandrine (8) is bioactivities of bisBIAs has largely increased. Several extensive the major bisBIA found in the roots of Stephania tetrandra studies have examined the antimicrobial and anti-allergenic (Menispermaceae), a climbing plant used in traditional Chinese characteristics of bisBIAs. The antiparasitic influence of twenty and Japanese medicine (Figure 3).25 Beyond its traditional use unique bisBIAs against Trypanosoma brucei and Leishmania for remedying autoimmune disorders, hypertension and donovani was explored by Camacho and co-workers.15 cardiovascular diseases, the pharmacological effects of Comparably, these alkaloids exhibited heightened synergistic tetrandrine have been the focus of various studies since the effects with the antibiotic cefazolin on methicillin-resistant late-1990s. The immunologic and vasodilatory properties of Staphylococcus aureus strains.16 tetrandrine have been well evaluated, particularly as a latent More recent findings have identified bisBIAs as inhibitors of therapeutic to treat drug-resistant autoimmune diseases and calcium influx in glial cells and neurons, combatting prevent excess fibrosis in patients with severe conjunctival neuroinflammation and neuroapoptosis.17 Another example by inflammation.26,27 Medeiros et al. reported that the alkaloid curine (10) induced The labs of Xu28 and Huang29 described the antiproliferative vasorelaxation via direct inhibition of L-type voltage-gated nature of tetrandrine (8) on human T and liver cancer cells, calcium current in rat aorta smooth muscle cells, triggering an respectively, by inhibition of NF-κB and calcium/calmodulin- intracellular decrease in transient calcium stores (Figure 3).18 dependent protein kinase II, both of which are critical regulators Of particular interest is the potential of these natural of not only innate immunity, but also cancer-related products as latent agents against the novel and highly inflammation. It was even found to upregulate in vitro pathogenic SARS-CoV-2, which is the fundamental cause of expression and activation of initiator and effector caspases in coronavirus disease 2019 (COVID-19). Plants of the glucocorticoid-resistant Jurkat T-cells, contributing to the Menispermaceae family are repeatedly used for the treatment apoptosis-inducing effect in T cell acute lymphoblastic leukemia of malaria as well as dengue fever and a number of isolated (T-ALL).26,30 alkaloids exert comparable antiviral consequences.19,20 He et al. Recently, the alkaloid has been recognized as an antagonist identified nine bisBIAs as potent in vitro SARS-CoV-2 entry of two-pore channels (TPC), or voltage-dependent calcium inhibitors.21 Tetrandrine (8) dramatically blocked viral S and N channels located on lysosomal membranes, which have been protein expression as well as human coronavirus OC43 (HCoV-

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suspected to be responsible for massive pulmonary edema and hemorrhage in mice models.39 Likewise, continuous administration of the alkaloid caused a marked pathological change in the liver tissues of dogs.40

3.2 Berbamine Berbamine (9) is a cyclic bisBIA isolated from the traditional Chinese herbal medicine Berberis amurensis (Figure 3).5 There is a well-documented history of its usage in clinical practice for treating inflammation, cancer, and autoimmune diseases.6 A simple keyword search in scientific databases returns about five hundred publications on berbamine’s pharmaceutical assessment spanning from 1969 to present day. Numerous findings have disclosed its inhibitory effects toward a variety of cancer cell lines, specifically advanced melanoma, ovarian cancer, and chronic myeloid leukemia.41 Its antiproliferative qualities are frequently associated with the inactivation of critical pro-tumorigenic pathways, such as p53, Fas signals, and Ca2+/calmodulin-dependent protein kinase II 훾.42 Interestingly, recent studies uncovered an unforeseen synergy of berbamine (9) with an assortment of targeted therapies. Zhao et al.43, Hu et al.44 and Jia et al.45 demonstrated that berbamine improved the efficacy of sorafenib, gefitinib and paclitaxel, respectively, on advanced hepatocellular carcinoma Figure 3. Selected bioactive bisBIAs. (HCC), pancreatic cancer and glioma cells through suppression of STAT3 signaling pathway and reactive oxygen species (ROS)- implicated in the pathogenesis of cancer and Ebola virus dependent phospho-Akt protein expression. infection.31 Sakurai et al. determined that in vivo and in vitro Ebola virus entry can be hindered by disrupting TPC channels 3.3 Neferine and dauricine using submicromolar concentrations of tetrandrine (8).32 The Neferine (12) and dauricine (13) are the primary bioactive alkaloid also reduced tumor metastasis through inhibition of components obtained from the seed embryo of Nelumbo TPC1 and TPC2 in vivo and in vitro.33 nucifera (lotus) and the roots of Menispermum dauricum (Asian An additional pharmacological target of tetrandrine (8) is P- moonseed), respectively (Figure 3).6,39 Both compounds display glycoprotein (Pgp), a ubiquitous membrane transporter with antiviral, antioxidant, antidepressant, antiarrhythmic and anti- the ability to efflux drug molecules out of cancer cells, which cancer actions.39 reduces the efficacy of chemotherapies.34 Overexpression of Neferine (12) has neuroprotective capabilities and can Pgp in cancer cells is a crucial factor of multi-drug resistance function as a ROS mediated autophagy inducer (Figure 3).46,47 toward a variety of antitumor agents. Among a series of bisBIAs, Its anti-diabetic implications were disclosed by Li and co- tetrandrine was identified as an effective modulator of Pgp workers.48 Their study revealed that compared to untreated activity.26,35 Named CBT-1, this alkaloid is being developed by diabetic mice, an evident reduction in the blood pressure, body CBA Research Inc. as an adjunctive therapy to chemotherapy in weight, fasting blood sugar glucose, insulin, triglycerides and various cancer types with multiple drug resistance, including total cholesterol was seen in type II diabetic mice upon neferine sarcoma, non-Hodgkin’s lymphoma, acute myelogenous treatment. Additionally, the alkaloid not only bolstered the anti- leukemia, and multiple myeloma.36 Prior phase I trials with CBT- tumor effects of chemotherapeutic agents, but also reversed 1 defined the tolerable dose range and side effects when multiple drug resistance in in vitro as well as in vivo models of administered with doxorubicin.37 The most recent clinical study cancer by decreasing epithelial-mesenchymal transition (EMT), is currently investigating the combination of doxorubicin and a process associated with chemoresistance and tumor CBT-1 for the treatment of unresectable, metastatic sarcoma in invasion.46,49,50 In a recent investigation, neferine reduced the patients who previously progressed with doxorubicin.38 A viability of human prostate cancer (PCa) cells and their stem thorough discussion of the synergistic, apoptotic, and cells in a time- and dose-dependent manner by upregulating autophagic consequences of tetrandrine on multiple cancers, cleaved PARP, apoptotic caspase-3, and downregulating the both in vitro and in vivo, is included in a comprehensive review expression of anti-apoptotic protein Bcl-2. Intriguingly, neferine by Luan et al.35 also elevated the expression of several tumor suppressor genes From a toxicity perspective, oxidative metabolism involving and downregulated cyclin-dependent kinase 4 (CDK-4) 51 the 12-O-methoxy group of tetrandrine (8) leads to the expression, leading to cell cycle arrest at the G1 phase. generation of a highly reactive quinone methide intermediate

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Scheme 1. a) Total synthesis of (±)-coclaurine (1) and b) Hiemstra’s strategy to access ten benzyltetrahydroisoquinolines (23).

Dauricine (13) exerts similar pharmacological attributes with sequence has since been adapted and modified in later clinical potential. Its cardiovascular, anti-inflammatory, syntheses of related tetrahydroisoquinolines. For example, N- membrane modulating, anti-platelet aggregation and methylcoclaurine (2) was obtained through a LiAlH4-mediated neurological effects are well-documented (Figure 3).5,6 Outlined reduction of the urethane derivative of dibenzylcoclaurine by Wang et al., dauricine (13) significantly minimizes the in vitro followed by hydrogenolysis.57 The Bischler–Napieralski reaction secretion level of amyloid beta (Aβ) and Cu2+-induced ROS in and a Noyori-type reduction is another representative synthesis human β-amyloid precursor protein (APPsw) cells.52 Hence, it is sequence often applied in the construction of these suggested that the alkaloid could rescue neurons from oxidative isoquinoline scaffolds. stress-induced apoptosis and possibly relieve acute oxidative Contemporary synthetic methods have been aimed at damage in Alzheimer’s disease (AD) models. The therapeutic utilizing N-acyl Pictet–Spengler reactions rather than the capacity of dauricine against lipopolysaccharide (LPS)-induced conventional Bischler–Napieralski protocols to provide the inflammatory bone loss is more recently demonstrated by Park tetrahydroisoquinolines directly, thus enhancing step- and co-workers via its action on osteoclasts (OC).53 Yet, the economy. In 2015, Hiemstra and co-workers reported an adverse cytotoxicity of the alkaloid in liver, kidney and lung- enantio- and regioselective Pictet–Spengler condensation derived cell lines is often overlooked.54 between aryl acetaldehydes (20) and o-nitrophenylsulfenyl (Nps)-substituted arylethylamines (21) using (R)-TRIP as the chiral catalyst (Scheme 1b).58 This method provided access to 4. Total syntheses of bisBIAs several 1-benzyl-1,2,3,4-tetrahydroisoquinolines with up to 4.1 Synthesis of coclaurine and its derivatives 92% enantiomeric excess. With this organocatalyzed Pictet– Spengler reaction, the Hiemstra group accomplished the Besides being structural fragments and precursors, the synthesis of ten biologically relevant tetrahydroisoquinoline synthesis of coclaurine (1) and its derivatives is imperative in alkaloids, including (R)-coclaurine, (R)-reticuline, (R)- accessing the dimeric bisBIAs. The original strategy of norprotosinomenine, and other variants. Illustrated in Scheme assembling coclaurine involved the condensation of 4- 2, the steps subsequent to the key (R)-TRIP-catalyzed Pictet– benzyloxy-3-methoxyphenylethylamine (15) with (4- Spengler reaction are high yielding and straightforward. O- ethoxycarbonyloxyphenyl)acetyl chloride (16), Bischler– Methylation of the resulting tetrahydroisoquinolines (22) using Napieralski cyclization of the resultant amide (17) to afford the MeI and K2CO3 followed by acid-mediated cleavage of the hydrochloride salt of dihydroisoquinoline 18, PtO -mediated 2 MOM, TBS, and Nps groups gave the alkaloids (23) as their reduction of the imine, and deprotection by acid hydrolysis hydrochloride salts in 71–89% overall yield with the ee’s being (Scheme 1a).55 An Arndt–Eistert reaction between amine (15) mostly preserved. The N-methyl derivatives were fashioned and 4-methylsulphonyloxydiazoketone has also been employed from the unprotected alkaloids via reductive amination with to synthesize amide 17 en-route to coclaurine (1).56 The above NaCNBH3 and formaldehyde.

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Scheme 2. Total synthesis of a) (±)-dauricine (13, no yields reported) and b) (+)-O-methylthalibrine (29).

4.2 Synthesis of acyclic bisBIAs approach was opted by Kametani and Fukumoto nearly one There exists two fundamental synthetic approaches to decade later for the first total synthesis of (±)-dauricine (13) and bisBIAs.8 One is to form diaryl ether bonds for tail-to-tail or its diastereomer using both the Arndt–Eistert homologation 62 head-to-tail connected bisBIAs, to which are subsequently and Bischler–Napieralski reactions (Scheme 2a). Other early elaborated to isoquinoline fragments (see Scheme 2). The synthetic iterations of magnolamine, daurinoline, magnoline second method is to prefunctionalize both benzylisoquinoline and berbamunine were obtained through reaction sequences units and then merge them via diaryl ether bonds. Nearly all analogous to Scheme 2a, all of which integrated Ullmann 63 syntheses of acyclic and cyclic bisBIAs to-date rely on the couplings as the key step with yields ranging from 4–20%. A classical intra- and intermolecular copper-catalysed Ullmann comparable tactic was chosen by Nishimura et al. for the reaction to generate mono- and (bis)ether linkages, synthesis of nelumboferine and three unnatural stereoisomers 64 respectively, despite its lack of efficiency: long reaction times, of neferine and O-methylneferine. Ullmann coupling of the high temperatures, stoichiometric amount of copper salts, and tetrahydroisoquinoline units with copper(I) bromide and Cs2CO3 low yields. Variations of the reaction utilizing nickel and in pyridine gave the respective dimers in 34–45% yields. palladium have relatively broadened the substrate scope and Modular strategies have been developed for the rendered the reaction conditions milder. Namely, modern enantioselective synthesis of bisBIAs. Both benzylisoquinoline alternatives such as the Chan–Evans–Lam reaction59 and units in the total synthesis of (+)-O-methylthalibrine (29) arose Buchwald–Hartwig coupling60 have been explored to assemble from 1,2,3,4-tetrahydroisoquinoline-1-carbonitrile (24), which the diaryl ether linkages. However, yields remain inconsistent was deprotonated with KHMDS and alkylated to provide 3,4- 65 for C–O bond formation, especially in the context of bisBIAs. dihydroisoquinolines 25a and 25b (Scheme 2b). Noyori One of the early pioneering efforts in the synthesis of the transfer hydrogenation, reductive N-methylation with NaBH4 acyclic bisBIA series was in 1955, when a scheme was devised and formaldehyde afforded bromobenzylisoquinoline 27 and for constructing O-methyldauricine via Ullmann coupling (+)-laudanidine (28) as the precursors for the final Ullmann between (–)-armepavine and (–)-3-bromo-O- coupling, which delivered bisBIA 29 in 51% yield. This protocol methylarmepavine, which was achieved in 24% yield.61 A similar was exploited for the asymmetric synthesis of bisbenzylisoquinoline derivative (+)-tetramethyl-magnolamine

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electrochemical constraints and reactants, the conditions for the anodic oxidation of phenol 32 and ensuing cathodic reduction of dimer 33 were developed for the preparation of (+)-O-methylthalibrine (29) and its derivatives (Scheme 3b). O- methylation and dehalogenation of dimer 34 yielded diacid 35. The phenylacetic acid moieties were then coupled to phenylethylamine derivative 36 bearing a chiral auxiliary to achieve two simultaneous asymmetric Bischler–Napieralski reactions. Substitution of the auxiliaries with methyl groups afforded (+)-O-methylthalibrine (29) in an overall yield of 29%. A recent total synthesis of (S,S)-tetramethylmagnolamine (46) featured a unique instance of catalytic aerobic desymmetrization that took advantage of the alkaloid’s inherent pseudosymmetry (Scheme 4).68 The synthesis commenced with the preparation of Boc-protected tetrahydroisoquinoline 42 via amidation of homoveratrylamine (38) and 4-hydroxyphenylacetic acid (39). The Bischler– Napieralski cyclization of the accompanying amide (40) permitted an asymmetric Noyori hydrogenation to deliver free amine 41 in 70% yield with 94% ee. Upon protection of the

amine (41) with Boc2O, the strategic aerobic oxidative coupling was realized by treatment with O2 and a catalyst system

Scheme 3. Electrochemical methods to synthesize a) (±)-dauricine (13) and b) (+)-O-methylthalibrine (29). BOP = benzotriazol-1- yloxytris(dimethylamino)phosphonium hexafluorophosphate. CCE = constant current electrolysis. as well as benzylisoquinolines (+)-laudanosine and (+)- armepavine. Although Ullmann cross-coupling reactions have been extensively applied in aryl ether syntheses, oxidative C–O bond forming reactions have been considered as green and cost- effective surrogates. The first preparation of a naturally occurring bisBIA using an electrolytic oxidation was described in 1971 by Bobbitt and Hallcher.66 When the sodium salt of (±)-N- carbethoxy-N-norarmepavine (30) was subjected to electrolysis using tetramethylammonium perchlorate as the electrolyte, a graphite anode together with a platinum cathode, a carbon– oxygen (31) linked dimer was obtained (Scheme 3a). Subsequent O-benzylation, reduction, and catalytic debenzylation, furnished a racemic and diastereomeric mixture of dauricine (13). To install the diaryl ether moieties of bisBIAs at an early Scheme 4. Huang and Lumb's synthesis of (S,S)- tetramethylmagnolamine (46). DBED = N,N’-di-tert- stage, Nishiyama and co-workers broadly surveyed electrolytic butylethylenediamine. phenol couplings.67 Following an extensive screening of

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comprised of CuPF6 and N,N’-di-tert-butylethylenediamine anhydride generated an imine, which was subsequently (DBED). Reductive workup then gave rise to the corresponding reduced to amine 50. N-methylation of the amine (50) provided catechol derivative (45). Methylation of 45 and reduction of the the dihalide (51). N-Boc groups supplied the dimeric alkaloid (46) over seven Analogous to the protocol shown in Scheme 2b, the second steps in 21% overall yield. A prior synthesis of 46 by Blank and MOM-protected benzylisoquinoline moiety (53) was Opatz required sixteen steps in 14% overall yield and employs a synthesized from aminonitrile 52 over three steps via an conventional Ullmann coupling to form the key diaryl ether.65 umpolung, alkylation-reduction sequence (Scheme 5b). The rather risky double C–O couplings of precursors 51 and 53 were performed under the reported Ullmann reaction conditions in 4.3 Synthesis of cyclic bisBIAs Scheme 5b. Finally, removal of the benzyl groups delivered (±)- Cyclic bisbenzylisoquinoline alkaloids constitute the more curine (10) and (±)-tubocurine (55) in a 2:1 diastereomeric ratio. prominent yet challenging class of this natural product family, The total synthesis of 55 also embodied the formal synthesis of especially in the context of establishing the appropriate diaryl (±)-tubocurarine (56). ether linkages. In 2017, Opatz and co-workers accomplished the racemic synthesis of (±)-curine (10) and (±)-tubocurine (55) based on two sequential Ullmann-type condensations (Scheme 5).8,69 Preparation of the dihalogenated building block (51) began with an amide coupling of phenylethylamine 47 and phenylacetic acid 48 (Scheme 5a). The Bischler–Napieralski reaction of amide 49 mediated by 2-chloropyridine and triflic

Scheme 6. Bracher’s modular total synthesis of (±)-tetrandrine (8) and isotetrandrine (58). Conditions for vital Ullmann couplings: CuBr•SMe2, Cs2CO3, pyridine, 110 °C; Pictet–Spengler reactions: TFA, CH2Cl2.

The aforementioned dual Ullmann reaction was similarly presented in a modular twelve-step synthesis to racemic tetrandrine (8) and its diastereomer isotetrandrine (58), Scheme 6).70 Presented in four distinct routes, each strategy incorporated N-acyl Pictet–Spengler reactions to access the 1- benzyltetrahydroisoquinoline units and copper-mediated Ullmann-type couplings for C–O bond formation. The first route provided the macrocyclic skeleton (57) using two alternating intermolecular Pictet–Spengler cyclizations and an intramolecular diaryl ether coupling. In the second route, an intramolecular N-acyl Pictet–Spengler condensation constructed the final alkaloid precursor (57). An additional variant for the above routes was also devised, whereby either of the aromatic ring systems (A–C or A’–C’) could be assembled

at the outset. The final step of all four variants was an LiAlH4- reduction of both carbamates in macrocycle 57 to obtain racemic mixtures of (R,R)/(S,S) tetrandrine (8) and (S,R)/(R,S) isotetrandrine (58) in 3–19% overall yields. The authors computationally analyzed the observed diastereomeric outcome of the key Pictet–Spengler cyclizations, which revealed that the stereochemistry at the C-1 stereocenter of the Scheme 5. Opatz’s synthesis of (±)-curine (10) and (±)-tubocurine (55), and formal total synthesis of (±)-tubocurarine (56). macrocycle helps to control the formation of the second chiral center of tetrandrine (8).

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Conclusions 18 M. A. A. Medeiros, J. F. Pinho, D. P. De-Lira, J. M. Barbosa-Filho, D. A. M. Araújo, S. F. Cortes, V. S. Lemos and J. S. Cruz, Eur. J. Existing approaches for the total synthesis of bisBIAs Pharmacol., 2011, 669, 100–107. underscore limitations in the current state-of-the-art. Not only 19 P. G. da Silva, A. H. Fonseca, M. P. Ribeiro, T. D. Silva, C. F. F. do the unique structures of bisBIAs serve as inspiration for the Grael, L. J. Pena, T. M. S. Silva and E. de J. Oliveira, Nat. Prod. development of practical synthetic protocols, but the Res., 2020, 0, 1–5. therapeutic properties of these compounds are also compelling 20 J. Bero, M. Frédérich and J. Quetin‐Leclercq, J. Pharm. and have spurred numerous efforts in analog synthesis. With Pharmacol., 2009, 61, 1401–1433. continual interest in the function of bisBIAs, advancing synthetic 21 C.-L. He, L.-Y. Huang, K. Wang, C.-J. Gu, J. Hu, G.-J. Zhang, W. Xu, Y.-H. Xie, N. Tang and A.-L. Huang, Signal Transduct. Target. strategies for practical access to enantioenriched bisBIA Ther., 2021, 6, 1–3. frameworks is warranted. 22 D. E. Kim, J. S. Min, M. S. Jang, J. Y. Lee, Y. S. Shin, C. M. Park, J. H. Song, H. R. Kim, S. Kim, Y.-H. Jin and S. Kwon, Biomolecules, 2019, 9, 696. Author Contributions 23 C. Bailly, Phytomedicine, 2019, 62, 152956. VKN and KGMK wrote the mini-review. 24 Z. Wang and L. Yang, Front. Pharmacol., 2020, 11, 1013. 25 N. Bhagya and K. R. Chandrashekar, Phytochemistry, 2016, 125, 5–13. Conflicts of interest 26 W. Xu, S. Chen, X. Wang, S. Tanaka, K. Onda, K. Sugiyama, H. Yamada and T. Hirano, Pharmacol. Ther., 2021, 217, 107659. There are no conflicts to declare. 27 A. Kitano, O. Yamanaka, K. Ikeda, I. Ishida-Nishikawa, Y. Okada, K. Shirai and S. Saika, Curr. Eye Res., 2008, 33, 559–565. 28 W. Xu, J. Kusano, S. Chen, R. Yamamoto, H. Matsuda, Y. Hara, Y. Acknowledgements Fujii, S. Hayashi, S. Tanaka, K. Sugiyama, H. Yamada and T. Hirano, Z. 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